Disrupted-In-Schizophrenia-1 (DISC1) is one of the most promising common susceptibility factors for major mental illnesses, such as schizophrenia and mood disorders. Our long-term goals are to clarify disease pathway(s) that commonly exist in major mental illnesses, especially schizophrenia. DISC1 appears to be a promising lead to advance analysis of the pathway(s). DISC1 protein is multifunctional with several distinct subcellular distributions, including the centrosome during neurodevelopment, the postsynaptic density, and the nucleus. Previous studies of autopsied brains and cell biology from our and other groups have suggested that DISC1 may have a regulatory role in gene transcription, which may be disturbed in major mental disorders. Thus, we hypothesize that study of a "nuclear" pathway of DISC1 may elucidate the pathophysiology of major mental illnesses. In Aim 1, we will determine biochemical mechanisms that regulate nuclear distribution of DISC1, focusing in particular on cis- elements and phosphorylation. In Aim 2, we plan to characterize protein interactions of DISC1 in the nucleus, focusing on ATF4/CREB2 (a transcription factor), N-CoR (a nuclear co-repressor), and PML (the main component of the nuclear body). We hypothesize that DISC1 functions as a scaffold at the nuclear body to recruit components of activator/repressor complex to CREB/ATF transcriptional machinery. Aim 3 is designed to elucidate mechanisms of how nuclear DISC1 regulates gene transcription, in particular CRE-mediated gene transcription. We hypothesize that possible recruitment of components of activator/repressor complex by DISC1 at the PML-nuclear body regulate CRE-mediated gene transcription at least via ATF4/CREB2. We hope that this mechanistic study will provide insight into understanding major mental illnesses and eventually lead to better therapeutic strategies for the diseases. PUBLIC HEALTH RELEVANCE: Disrupted-In-Schizophrenia-1 (DISC1) is one of the most promising common susceptibility factors for major mental illnesses, such as schizophrenia and mood disorders. Because several lines of evidence have suggested "nuclear" DISC1 may be involved in the pathophysiology of the diseases, we will study basic mechanism and regulation for "nuclear" DISC1. We will particularly focus on the key mechanisms that regulates nuclear functions of DISC1, including cis-elements for nuclear targeting, phosphorylation, SUMOylation, and protein interaction with other nuclear proteins, as well as its function in gene transcription.